TW200846340A - Methods for preparing eszopiclone - Google Patents

Abstract

Methods for the preparation of crystalline eszopiclone free base in water, in the absence of organic solvents, are provided. The methods are more environmentally acceptable than prior art methods, and produce eszopiclone free base essentially free of residual organic solvent.

Description

200846340 IX. Description of the invention: [Technical field to which the invention pertains] The present invention relates to a method for preparing zopiclone. This application claims the following U.S. Provisional Patent Applications: No. 60/898,405, filed on January 31, 2007; No. 60/929,682, filed July 9, 2007, and 11/2007, filed on April 20, 2007 738, 115. The contents of such applications are incorporated herein by reference. [Prior Art] Zopiclone, a non-benzoic acid I for the treatment of insomnia, which can be used to induce sedation, hypnosis or sedative effect, has the chemical name 'methylpiperazinecarboxylic acid 6_(5-chloro-2♦-based)卜^: Hydrogen^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ Oxy _ 5 Η 吼嘻 [ [3, 4 仲 唤 _ 5 to 'methyl piperidine small formic acid vinegar or pyridin-2-yl)-5- (4-methylpiperazin-1-yl) carbonyl oxygen The radical _7_sideoxy_6 'monohydro-5H-pyrrolo[3,4-b]pyridazine racemate is represented by the following.

Zopiclone is the S-enantiomer of zopiclone and is more active and less toxic than the racemic zopiclone of U.S. Patent No. 128,855.doc 200846340 6,444,673 B1. The drug, formerly known as Estorra®, is marketed in the United States by SepracorTM under the name Lunesta0. Zopicl has the chemical name (+)-6-(5-chloro-2-pyridyl)-7(S)-(4-methylpiperazin-1-ylcarbonyloxy)-6,7_two Hydrogen-5H-indolo[3,4-b]pyridazin-5-one, CAS Registry No. 138729-47-2, and is represented by Formula II below.

The zopiclone of the ch3 II in the form of the free base and the salt form is disclosed in U.S. Patent Nos. 6,444,673 and 6,864,257. Zopiclone can be prepared by optical resolution of racemic zopiclone. U.S. Patent No. 6,444,673 discloses a process for the preparation of zopiclone free base by the preparation of D-(+)-oxime, CT-dibenylhydrazine-tartrate, followed by two crystallizations in a gas purge. The zopiclone salt is neutralized with an aqueous solution of sodium hydroxide to obtain a two-phase system, the organic phase is separated, the organic phase is evaporated to dryness, and the product is crystallized from acetonitrile.

Blaschke, G. et al., Chirality (1993) 5: 419-421 discloses the preparation of zopiclone without enantiomers using 0.5 equivalents of D-(+)-malic acid. From this procedure, the diastereomeric salt was crystallized from a decyl alcohol-acetone mixture, followed by neutralization of the salt with KHCO3, and the free base was extracted from ch2C12 / ethyl acetate and lysed by concentrating the solution. 128855.doc 200846340 U.S. Patent No. 6,339,086 uses 1 equivalent of 〇-(+)... malic acid to improve the use of malic acid to prepare zopiclone by optical resolution of racemic zopiclone. This patent discloses a process for preparing zopiclone free base by heating the mixture to about 65 by neutralizing the zopiclone D-(+)-malate with a KAO3 aqueous solution in a mixture of water and ethyl acetate. 〇; separation of the organic phase; Han shrink and separation to prepare. US 2005/0043311 discloses optical resolution of D-(+)-dibenzimidyl-tartaric acid to obtain a zopiclone salt, neutralizing the salt in the presence of an aqueous solution of dioxane & Na〇H, and isolating the organic phase. And evaporating it to obtain zopiclone. Subsequently, zopiclone was crystallized from acetonitrile. Recrystallization of zopicl clones using various organic solvents has been disclosed in US 2007/0270590. The solvent examined allowed the crystalline zopiclone to have a residual organic solvent [JD1] even after vacuum drying. The present application claims the benefit of the U.S. Provisional Application filed herewith. This technique is used to reduce the volume of solvent used in the method, using the ring _ 丨 brother, not to mention, the agent and energy saving, and the zopiclone free base is prepared by increasing the yield at a lower temperature. There is a need for a method. There is also a need for a process for making zopiclone having a reduced level of residual organic solvent. [Invention] In one embodiment, the invention provides a method of obtaining zopiclone comprising combining at least one salt of zopiclone with water and at least one base. In one embodiment, the invention provides a method of obtaining zopiclone comprising reacting a salt of zopiclone with a base in a single phase reaction mixture comprising water to obtain zopiclone. 128855.doc 200846340 In another embodiment, the invention provides a method of preparing zopiclone comprising reacting a salt of zopiclone with a base in water in the absence of an organic solvent to obtain zopiclone. In another embodiment, the present invention provides a method for improving the color of zopiclone by treatment with activated carbon, which comprises dissolving a salt of zopiclone in water; and adding activated carbon. In another embodiment, the invention provides zopiclone having less than about 5000 ppm residual organic solvent. ^ f施方式] As used herein, "zopiclone" refers to zopiclone free base. As used herein, the term " ambient temperature" means about 2 (rc to about 25 of its temperature. As used herein, the term "weak base" means having about 13 or less, preferably about 12 Preferably, the test is selected from the group consisting of ammonia 'single-single amine, dialkylamine or trialkylamine> (each of which is a test) The alkyl group preferably has 1 to 6 carbon atoms, and more preferably! to 3 carbon atoms 'and more preferably methyl or ethyl), an alkali metal carbonate, a soil metal carbonate, a metal hydrogencarbonate and Soil test metal hydrogencarbonate and its combination. More 'total metal carbonates and alkali metal hydrogencarbonates, preferably carbonic acid: and carbon, strontium potassium and sodium bicarbonate and (four) hydrogen potassium. Preferred alkali towel cationic material when When it is paired with the zopiclone salt to form an anionic substance, water=salt salt will be produced. In the prior art, D_(+), an acid salt or d_(1)-dibenzoyl-tartrate salt of zopiclone is prepared. The method of cloning includes extracting zopiclone from the aqueous phase under 絵: sexual conditions in a two-phase system 128855.doc 200846340. The method described in U.S. Patent No. 6,339,086 requires a large amount of solvent to draw the material from the aqueous phase. To reduce the volume of the solvent, the extraction is carried out at a higher temperature. Therefore, 'attributed to under alkaline conditions and under heating Subsequent compound degradation 'The yield of these methods is low. In addition, the optical purity of the product is affected' because the isomerization process occurs under the conditions of the test and under heating. Residual solvent. The present invention provides an improved method for obtaining zopiclone comprising neutralizing a salt of zopiclone with 35, preferably a weak base in water at ambient temperature, in particular zopiclone D malate, avoiding as in prior art In the procedure, the sub-pile is obtained by directly filtering the obtained zopiclone by filtering from the water, a step of exposing the substance to heat and/or minimizing the test, as the case may be followed by carbon treatment before the addition test. Good color. The method of the present invention allows for production at a higher productivity than the methods of the prior art. #组合, and add at least - silk φ & ^ double. It is also possible to first add the base to the water, and then make a single-phase reaction mixture with the zopiclone and water. The section is composed mainly of water, ±, the method does not use organic solvent, especially The water-immiscible organic solvent is not used. J The salt of euploidin is in the water ^ ^ m -. Preferably, the bromo is about "about one to about three." The salt may be an acid salt (organic or inorganic), preferably. Optically active, salt of acidity 128855.doc -10- 200846340 The salt may be a water-soluble salt. The line is preferably a water-soluble active acid, such as, for example, a malate. Other examples of organic optically active acid salts are: 匕(+)·0,0-xylenemethanyl-tartrate, D-(1)-tartrate, D-(+)-mandelate, and D_(+)_ 〇, 〇, _ dibenzimidyl tartrate. When the salt is not a water-soluble salt, a liquid is obtained. When the salt is a water soluble solution. The temperature during the post-test and salt reaction is preferably from about 5 Torr to about 约, more preferably from about ambient temperature to about 50 Å. (:, preferably about R, w, and 1 soil, and the temperature around the crucible to about 40 ° C, and the best is about the ambient temperature. Double moon il rut 4 soil to > valley > night added Active charcoal. It is preferred to give off (4) containing activated carbon. _ (four) material about 5 hours, more preferably about 3 hours' and optimally about 1 hour. After stirring and adding alkali: better removal activity Carbon is preferably removed by hydrazine. The base is preferably an organic and inorganic weak test. The weak test is preferably an inorganic test. The test is optional = the group of the following components: ammonia, alkaline earth metal hydroxide, metal test a metal carbonate, a soil metal carbonate, a metal carbonate, a soil metal hydrogencarbonate, and an amine. The metal is preferably selected from the group consisting of potassium and sodium/salt salts, preferably selected from potassium carbonate and a group consisting of sodium carbonate. The hydrogen hydride salt is preferably sodium hydrogencarbonate or potassium hydrogencarbonate. At least one of the formulas may be added in the form of a solid or an aqueous solution, and the organic base is preferably added. Inorganic base of the plant. Preferably, the stepwise addition of at least one inorganic base is preferably about 1 hour to about 3 hours, more preferably An aqueous solution of at least one inorganic base is added to the keeper from about 2 hours to about 3 hours. The desired pH after the addition of the base is from about 7 to about 12, preferably about 8. 128855.doc 200846340 After the addition test, a suspension is obtained Preferably, the suspension is scrambled for a period of time after the addition of the base. The agitation preferably takes from about 1 hour to about 24 hours' and more preferably from about 2 hours to about 4 hours. Zopiclone. Preferably, the isolated zopiclone can be further washed and dried. Preferably, it is washed with water: preferably, the drying system is under vacuum (less than 100 mmHg). 30 C to about 80 ° C, more preferably from about 40 ° C to about 70 ° C, optimally at a temperature of about 50 ° C. The dryness is preferably from about 6 hours to about 16 hours. A method for improving the color of zopiclone by treatment with activated carbon, which comprises dissolving a salt of zopiclone in water; and adding activated carbon. The salt of zopiclone is preferably a water-soluble salt, and more preferably optical/tongue. A water-soluble salt of hydrazine, such as malate. Improving color means removing Color impurities, such that the obtained zopiclone is whiter. The parameters of the method are as described above. The method of the present invention can produce crystalline zopicl clone. The crystalline form is Form A disclosed in Φ 2〇〇7/〇270590, This patent is incorporated herein by reference. Zopicone Form A is a crystalline zopiclone characterized by the following major XR_: 20 being 5.1, 10.1, 11.3, 12.6, 1 U, .18", H1, 20·2 , 21·4, 25·7, 27.7+-0.2 degrees. The present invention also provides that the residual organic solvent is less than that recommended by, for example, the ICH guidelines and the pharmaceutical products as stated in the US Pharmacopoeia. The amount of ethyl acetate and isobutyl acetate is less than 5 〇〇〇, in terms of toluene, /, at 800 and isopropanol, less than 5 〇〇〇 ppm, and the mile is preferably less than About 5 〇〇〇ppm [jD2] residual organic solvent, preferably 128855.doc 200846340, more preferably less than about 2000 ppm residual organic solvent, most preferably less than about 700 ppm. The optical purity of zopiclone is preferably greater than about 99.9. %. The pharmaceutical composition can be prepared by combining zopiclone having a low residual solvent with at least one pharmaceutically acceptable carrier. Pharmaceutical compositions can be formulated into dosage forms such as lozenges and capsules and administered to a patient to induce sleep. Zopiclone with a low residual solvent can also be used to make drugs that induce sleep. The invention has been described with reference to certain preferred embodiments thereof, and other embodiments thereof will become apparent to those skilled in the art. The invention is further defined by reference to the following detailed description of the preparation of the composition and the use of the invention. It will be apparent to those skilled in the art that many improvements in materials and methods can be practiced without departing from the scope of the invention. Experimental methods and instruments: HPLC method for chemical purity determination:

HPLC Columns and packing: Buffer preparation: Eluent A: Eluent B: Eluent gradient: Stop time: Equilibrium time: Flow rate: Detector: Injection volume: Thinner:

Inertsil ODS 3V 25〇χ4.6 mm 5μ CN 5020-01802 0.01 Sodium dihydrogen sodium hydride is adjusted to pH = 7·0 with 1 N NaOH 66% buffer: 34% acetonitrile acetonitrile time (min) leaching agent A (° /〇) Dissolving agent B (%) 0 min 1000 13 min 1000 23 min 4060 33 min 4060 33 min 7 min 1.0 ml/min 306 nm 201 50% acetonitrile·· 50% buffer 128855.doc -13- 200846340 Temperature: 250. . Autosampler temperature: 100 °C HPLC Column and packing DAICEL Chiralcel OD-H 250x4.6 Dissolving agent: 0.1% DEA in ethanol Stop time: 25 min Flow rate: 0.7 ml/min Detector _· 306 ran Injection volume: 20 μΐ Thinner: Ethanol column temperature: 25〇C Autosampler temperature: 10°C 5 μηιΟΝ: 14325

Chromatographic conditions for measuring residual solvent amount:

Column: DB-624, 30 mx 〇.53 mm ID, 3 μιη film thickness (J&W 125-1334) or equivalent carrier gas: helium, about 3.7 psi, constant pressure (about 5 mL/min, 40 〇Injection mode: Headspace, split split ratio: 1:5, using COMBI PAL (CTC Analytics) headspace sampler (gas injector system) 1:20, using HP-7694/Agilent G1888 headspace sampler system (pressure / Loop System) $ Flame Ionization Detector Detector: Supplemental Gas: Nitrogen Oxygen 'approx. 25mL/min Temperature: Headspace Injection System Syringe: 180°C Detector·· 260°C Flood Box Program: Starting Temperature: 4〇°C Start time: 3.0 min Final temperature final time ^C/min 140°C 5.0 min Use one of the following headspace sampler systems···························· Gas injector system) Syringe: 2.5 mL Sample volume: 1 mL Constant temperature: 80 °C Constant temperature: 35 min 128855.doc -14- 200846340 Stirring speed '· 500 rpm Stirring time: 5 s Stirring stop time: 5 s Syringe temperature · 100 c Filling speed: 300 pL/s Pull-out delay: Is injection speed : 800+L/s Delay before injection: 〇s Delay after injection: 1.5 s Syringe wash · 2.5 min GC run time: 24 min* 2·2· HP-7694/Agilent G1888 headspace sampler system (pressure/circuit system

Vial pressure: 12.5 psi Temperature: Oven: 80°C Circuit: 100°C Conveying line: 110°C Time: GC cycle: 24 min* Sample balance: 35 min Pressurization: 0.20 min Loop filling: 0.10 min Loop balance : 0.05 min Injection: 0.50 min Oscillation: 1 (low) Loop volume: :1 mL *Note: GC cycle time varies with room temperature, so it can be adjusted. Sample Preparation The sample was dissolved in disulfoxide, approximately 100 mg in 1 mL. EXAMPLES Example 1 - Suzopolone neutralization method with D_(+)-zopiclone malate was obtained with improved color [JD3] to D-(+)-zopiclone malate (1.0 g, 1.87 mmol, The optical purity (98.01%; purity distribution 99.91%) was added with activated carbon (0.1 g) in a solution of 20 ml of water. The mixture was stirred at 25 ° C for 1 hour. The stock solution was removed by filtration to remove the mother liquor by adding 40% aqueous potassium carbonate solution (0,6 mi, 2.3 mmol) with stirring. The suspension was stirred under it for 2 hours. The solid was filtered, washed with water and dried under vacuum at 5 ° C overnight to give 0.65 g (90 / 〇) zopicone ( optical purity 9812%, chemical purity distribution 99.94%) 〇 Example 2 - by D_(+) _ zopiclone malate to obtain zopiclone neutralization method φ under stirring 'by adding 40% aqueous potassium carbonate solution (2.9 ml, 11.6 mmol) to make D-(+)_zopiclone malate (5 〇 g, 9 35 mm 〇 1, optical purity 98.46%; purity distribution 99 92%) alkalized in 1 〇〇 - water solution. The suspension was stirred at 30 ° C for 4 hours. The solid was filtered, washed with water and dried under vacuum at 50 C overnight to give <3>3 g (91%) of zopicion (98.12% optical purity, 99.94%). Example 3 - Obtaining zopiclone from D-(+)-zopiclone malate. Neutralization method φ D-(+)- was added by stirring with an aqueous solution of potassium carbonate (2,9 ml, 11.6 mmol). The solution of zopiclone malate (5〇g, 9.35 mm〇1, optical purity 98.46%; purity distribution 99.92%) in 100 mi of water was alkalized. The suspension was stirred at 40 ° C for 2 hours. The solid was filtered, washed with water, dried, and dried under vacuum at 50 C overnight to yield 3.2 g (88%) of zopicone (98.20%, purity purity: 99.96%). Example 4 - The zopiclone neutralization method was obtained from D-(+)-zopiclone malate. The mixture was mixed under a tax by adding 40% aqueous solution of 3% water (2.9 ml, 11.6 128855.doc -16 - 200846340 mm〇 l) A solution of D-(+)-zopiclone malate (5. 0 g, 9.3 5 mmol, optical purity 98.46%; purity profile 99, 92%) in 100 ml of water was basified. The suspension was at 25. (The mixture was stirred for 2 hours. The solid was filtered, washed with water] and dried under vacuum at 5 ° C overnight to give 3.3 g (91%) of zopicone (optical purity 98.12%, chemical purity distribution 99, 94%). 5_The zopiclone neutralization method was obtained from D-(+)-zopiclone malate. _ Under the mixing, D-(+) was made by adding 25% aqueous sodium carbonate solution (4 〇ml, 116 mmol). _ zopiclone malate (5 〇g, 9.35 mm 〇 1, optical purity 98.46%; purity distribution 99.92%) basified in a solution of 1 〇〇 ml of water. The suspension was at 25 ° C The mixture was stirred for 2 hours. The solid was filtered, washed with water, and then dried under vacuum, and dried under vacuo to give 3.5 g (97%) of zopicone ( optical purity 98.15%, chemical purity distribution 99.94%). !>-(+)-zopiclone malate to obtain zopiclone neutralization method • EK+) by adding 40% aqueous potassium carbonate solution (2·6 ml, 1〇.3 mmol) with stirring The zopiclone malate (5 〇g, 9.35 mm 〇i, optical purity 98.46%; purity distribution 99.92%) was alkalized in 1 〇〇 ml of water. The suspension was stirred at 25 ° C for 2 hours. The solid was filtered, washed with water and dried under vacuum (d) to afforded to afforded 3.3 g (91%) of zopicone ( optical purity 98. 17%, chemical purity distribution 99.95%). Example 7 - Obtaining zopiclone from D-(+)-zopiclone malate. Neutralization method by stirring 40% aqueous potassium carbonate solution (3·5 ml, 14. 〇128855.doc • 17-) 200846340 mmol) basification of D-(+)-zopiclone malate (5 〇g, 9.35 mm optical purity 98.46%; purity distribution 99 92%) in 1 〇〇ml water . The suspension was stirred at 25 ° C for 2 hours. The solid was filtered, washed with water and dried under vacuum at 50 ° C overnight to give 3-4% (yield: 94%) zopicone (light purity 98. 17%, chemical purity distribution 99.91%). Example 8 - Obtaining zopiclone from D-(+)-zopiclone malate. Neutralization method by scrambled 'D-(+) by adding 40% aqueous potassium carbonate solution (2 9 ml, 116 mmol) A solution of zopiclone malate (5 〇g, 9.35 mm 〇1, optical purity 98.46%; purity distribution 99.92%) in 75 ml of water was basified. The suspension was stirred at 25 ° C for 2 hours. The solid was filtered, washed with water and dried in vacuo at 50 C overnight to afford <RTI ID=0.0>>> Example 9 - Obtaining the zopiclone neutralization method from |>-(+)... zopiclone malate. Under tax mixing' D- by adding 4% aqueous potassium carbonate solution (2.9 mi, .6 mmol) (+) _ zopiclone malate (5 〇 g, 9.35 mm 〇 1, optical purity 98.46%; purity distribution 99.92%) basified in 50 ml of water. The suspension was at 25. Stir under the arm for 2 hours. The solid was filtered, washed with water and dried in vacuo at 50 C overnight to afford <RTI ID=0.0>>> Example 10 - Obtaining the zopiclone by D-(+)_Zoppionyl malate The neutralization method was carried out by adding solid sodium carbonate (1.97 g, 186 mmol) to 128855.doc -18- 200846340 D () The solution of zopiclone frequency acid (go g, 1 $ · 6 mm 〇1, optical purity 98.46%, purity distribution 99.92%) in 160 ml of water. The suspension was stirred at 25 ° C for 2 hours. The solid was filtered, washed with water and dried under vacuum at 50 ° C overnight to afford 5·4 g (93%) Example 11 - Obtaining zopiclone from D_(+)-zopiclone malate. Neutralization method 1 M+)-zopiclone malic acid was added by stirring with 40% aqueous potassium carbonate solution (14.3 ml, 57 mmo1). The solution of the salt (24.6 g, 46 mmol) in 250 ml of water was basified. The suspension was stirred at 25 ° C for 20 minutes. The solid was filtered, washed with water, dried under vacuum at 50 ° C overnight and afforded 17 g (95%) of zopicone (chemical purity distribution 99 98%) with crystal form a. Example 12 - Zopicone was obtained from D-(+)-zopiclone malate by slowly adding a base. Neutralization method to D-(+)-zopiclone malic acid in 1 hour under stirring Sodium carbonate (3·76 g, 35 mmol) was added in several portions of a solution of salt (15 g, 29 mmol) in 300 ml of water. During the addition, the temperature rose from room temperature to about 35. (: The suspension was allowed to stand at 2 5 C for 2 hours. The solid was transferred, washed with water; and dried under vacuum at 40 ° C overnight to provide 9·59 g (yield 90.5%) of zopiclone. 13-Repeated Example 2 of U.S. Patent No. 6,339,086, under the agitation, at 30 ° C, to the zopicl malate (2.0 g, 3.74 mmol, HPLC purity distribution of 99.96% and HPLC optical purity of 96%) 40% aqueous potassium carbonate solution (1.6 g, 4.64 mmol) was slowly added to a mixture of water (4 ml) and ethyl acetate (20 ml). The mixture was then heated at 60 ° C, 128855.doc 19-200846340 'And the organic phase was separated and washed with 20 ml of water. The mixture was concentrated to 2/3 volume of organic solvent. The resulting slurry was cooled to 5 ° C and stirred at the same temperature for a further 2 hours. The solid was filtered using cold acetic acid The ethyl ester was washed and dried under vacuum at 50 C overnight (first dry) to give zopiclone with a HPLC optical purity of 9.65% of residual ethyl acetate containing 7534 ppm (GC). 75 It was further dried under vacuum for 18 hours (second drying) to give a content of 7360 ppm (GC). Exoethyl acetate, zopiclone. Example 14 - Method using a method similar to the method of Example 2 of U.S. Patent No. 6,339, 〇86, using other organic solvents, at 30 ° C, zopiclone apples were stirred at 30 ° C The acid salt (2 〇g, 3 74 mmol, HPLC purity distribution of 99.96% and optical purity 96%) was slowly added with 40% carbonic acid in water (4 ml) and one of the organic solvent mixtures shown in the table below. Potassium aqueous solution 〇·6 g, 4 64 mm〇1). The mixture was then heated and the organic phase was separated and washed with 2 mL of water. ^ Suture mixture. The slurry was cooled to 5. And stirred at the same temperature for another 2 hours. The solid was filtered, washed with a cold organic solvent (as previously used), and dried under vacuum overnight (first dry) to obtain zopiclone containing residual solvent. The zopicl was cloned at 75. (: further drying under vacuum) for 8 hours (second drying), again producing zopiclone containing residual solvent. Examples 13 and 14 (including by neutralization, extraction with organic solvent and precipitation from zopiclone malate The results of the preparation of zopiclone are shown in the following table. 128855.doc •20- 200846340 Organic solvent volume per gram of starting zopiclone (ml) Heating temperature (extraction period) (°C) Yield (%) Recovery rate* (%) Chemical purity (%) —·—— Optical purity (%) Residual solvent after first drying (ppm) Residual solvent after second drying (ppm) Ethyl acetate%4t 20 60 〇A 80 96.35 7534 7360 Acetate Butyl 80 73 Unchecked 96.4 6733 6468 Benzene 25 80 75^ ~ Unchecked 99^ Isobutyl acetate 64 80 60-96.8 8025 7478 83 99.94** 99.15 7799 7578 Recovery rate 14 zo The total amount of cloning (in solid form and in the mother liquor). **Material balance of zopiclone: the yield of the substance in the solid and mother liquor in these experiments is less than 83%, and the purity distribution of the substance dissolved in the mother liquor Is about 95% / indicates The zopiclone was decomposed. In the aqueous phase, zopiclone was absent. Example 1S - Crystallization of zopiclone from different organic solvents - The starting material of Example 15 was prepared according to one of the m-l_u. (10) 4] is shown in the table below. (Experiment was purified by crystallization; the zopiclone was filtered and neutralized from the organic solvent after neutralization of the zopiclone salt (usually zopiclone malate in water in the presence of a base).) Residual solvent solvent in zopiclone prepared by crystallization, volume of zopiclone (ml/gr), Ψ ^^FTrwi --- yield (%) chemical purity (%) of zopiclone product Optical purity of the clone (%) Optical purity of the zopiclone product (%) Residual solvent (ppm) [JD5] Acetic acid iso _90 99.97 98.85 99.96 1349 Isopropanol / water ' 5:1 (14) —--- _ 80 ~ 99.95 ~ 98.85 99.97 568 85 99.97 95.50 99.91 676 Example 16 - Preparation of zopiclone by agitation in water by neutralization in water, filtration and crystallization from 128855.doc * 21 - 200846340 organic solvent at 30 At °C, zopiclone malate (2.0 g, 3.74) A 40% aqueous solution of potassium carbonate (1.6 g, 4.64 mmol) was slowly added to a mixture of EtOAc (m. The solid was filtered, washed with water and dried overnight at 50 ° C (first dry) to obtain zopiclone. The zopiclone was further dried under vacuum at 75 ° C for 18 hours (second drying) to produce zopiclone containing the residual solvent. The zopicl clone was further crystallized from an organic solvent to produce zopiclone containing the residual solvent according to the following table. The product was further dried at 50 ° C to give a crystalline zopiclone containing the residual solvent according to the following table. The results of this experiment are shown in the table below. The purity of the zopiclone product (%) by the crystallization of the residual solvent solvent in the zopiclone prepared by crystallization (v/g) yield (%) The optical purity of the zopiclone (%) Optical purity (%) of zopiclone product Residual solvent (ppm) Benzene (9) 90 99.97 98.85 99.96 1349 Isobutyl acetate (27) 80 99.95 98.85 99.97 568 Isopropanol / water, volume ratio 5: 1(14) 85 99.97 95.5 99.91 676 128855.doc 22-

Claims (1)

200846340 X. Patent Application Range: 1. An eszopiclone having a residual organic solvent of less than about 5 〇〇ό ppm [JDl]. 2. The zopiclone of claim 1 which has a residual organic solvent of less than about 2000 ppm. 3. The zopiclone of claim 2 having less than about 700 ppm of residual organic solvent. 4. The zopiclone of claim 1, wherein the organic solvent is isobutyl acetate or isopropanol. 5. A method of equipping a zopicl clone which comprises reacting a salt of zopiclone with water in a test to obtain zopiclone. 6. A method of preparing zopiclone comprising reacting a salt of zopiclone with a base in a single phase reaction mixture comprising water to obtain zopiclone. 7. The method of claim 6, wherein the method is carried out in the absence of an organic solvent. 8. The method of claim 6, wherein: μ: φ 丄 丄 卞 - 卞 士 | | | 〒 The method is carried out in the absence of a water-immiscible organic solvent. 9. A method according to any one of claims 5 to 8, wherein the salt is a T1 term, wherein the acid salt of the zopiclone. I 〇 An active acid salt as claimed in any one of claims 5 to 8. II. For example, any of the water soluble salts of items 5 to 8. The method of any one of claims 5 to 8, wherein the zopiclone is an optical method, wherein the zopiclone salt is a method of the member, wherein the zopiclone salt is 128855.doc 200846340 The following groups of components: D_(+)_〇, 〇-dibenzhydryl-tartrate, D-(+)-tartrate, D_(+)·mandelate, D_(+)_〇 , 〇i· benzoyl decyl tartrate and D_(+) _ malate. 13. The method of claim 12, wherein the salt of the zopiclone is (ten)-malate. 14. 15. The method of any one of claims 5 to 8, wherein the temperature is between about 5 ° C and about 5 ° C. The method of any one of claims 5 to 8, wherein the method of any one of items 5 to 8, wherein the base reacts with the salt, wherein 5 is a weak test. Wherein the base is organic or inorganic. 17. The method of any one of claims 5 to 8, wherein the test is selected from the group consisting of ammonia, alkali metal hydroxides, alkaline earth metals , metal carbonate, soil metal carbonate, metal salt, alkaline earth metal hydrogencarbonate and amine. 18. A group of methods as claimed in claim 17. Wherein the test metal (iv) is free of potassium and sodium, wherein the test is selected from the group consisting of carbonic acid, wherein the test is sodium hydrogencarbonate or the pH of the base is added thereto. 19. The method of any one of claims 5 to 8 is used for potassium and carbonic acid. A group of sodium. 20. The method of any one of claims 5 to 8, potassium hydrogencarbonate [JD2]. The method of any one of claims 5 to 8 is from about 7 to about 12. 22. The method of claim 21, wherein "A far pH value of about 8 further comprises a score of 2 3 · If the item is from $ to 8 any one of the points is a < Wanfa, its 128855.doc 200846340 Addition of the test. The zopiclone has a small size. 24. The method of any one of claims 5 to 8 wherein activated carbon is added to the solution. 25. In claims 5 to 8 The method of any one of which is a residual organic solvent of 5 〇〇〇 PPm [JD3]. The method of claim 25, wherein the zopiclone has a residual organic solvent of less than about 2000 ppm. 27. The method of claim %, and the zopiclone has a residual organic solvent of less than about 7 〇〇 ππι. 2 8 The method of any of _ js ^ > wherein the zopiclone has an optical purity of greater than about 99, 9%. 29. Two methods for improving the color of zopiclone by treatment with activated carbon, which comprises dissolving D(+)-zopiclone salt in water; and adding activated carbon. 30. The method of claim 29, wherein the salt of zopiclone is monomethylglyoxime-tartrate, D_(+)-tartrate, D_(+)-almondine salt, D-(+)_ Malate and D_(+y〇, 〇, _diphenylmercapto tartaric acid. 31. A pharmaceutical composition comprising zopiclone according to any one of claims 1-4 and at least one pharmaceutically acceptable A method of inducing sleep in a patient, comprising administering to the patient a pharmaceutical composition according to claim 31. 33. Use of the pharmaceutical composition of claim 3, for use in manufacturing A drug for inducing sleep. 34. A pharmaceutical composition according to claim 3, which is used for inducing sleep. 128855.doc 200846340 VII. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) A brief description of the symbol of the figure: 8. If there is a chemical formula in this case, please reveal the chemical formula that best shows the characteristics of the invention: 128855.doc